ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.1263_1264insTCCCTCCTACCACCTGTACTACGGCGCCTCGGCCGGCTCCTACCAGTTCTCCATGGTGGGCGGC (p.Glu422fs)

dbSNP: rs1569001972
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV001290701 SCV001478838 likely pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2021-01-12 reviewed by expert panel curation This late frameshift insertion is not expected to result in nonsense mediated mRNA decay, but will alter the transactivation domain/inhibitory domain/VWRPY motif and elongate the protein [PVS1_strong]. It is absent from gnomAD (v2 and v3) [PM2]. The variant has only been reported in one proband with AML, however the germline origin is unclear (SCV000807758.1). It is of note that other C-terminal frameshift variants have been reported with some showing loss of transactivation ability and a dominant-negative effect (PMID: 14615365, 19808697, 25840971). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong and PM2.
PreventionGenetics, part of Exact Sciences RCV000680387 SCV000807758 likely pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing

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